Comparing data mining methods on the VAERS database

PURPOSE: Data mining may enhance traditional surveillance of vaccine adverse events by identifying events that are reported more commonly after administering one vaccine than other vaccines. Data mining methods find signals as the proportion of times a condition or group of conditions is reported soon after the administration of a vaccine; thus it is a relative proportion compared across vaccines, and not an absolute rate for the condition. The Vaccine Adverse Event Reporting System (VAERS) contains approximately 150 000 reports of adverse events that are possibly associated with vaccine administration. METHODS: We studied four data mining techniques: empirical Bayes geometric mean (EBGM), lower-bound of the EBGM's 90% confidence interval (EB05), proportional reporting ratio (PRR), and screened PRR (SPRR). We applied these to the VAERS database and compared the agreement among methods and other performance properties, particularly focusing on the vaccine-event combinations with the highest numerical scores in the various methods. RESULTS: The vaccine-event combinations with the highest numerical scores varied substantially among the methods. Not all combinations representing known associations appeared in the top 100 vaccine-event pairs for all methods. CONCLUSIONS: The four methods differ in their ranking of vaccine-COSTART pairs. A given method may be superior in certain situations but inferior in others. This paper examines the statistical relationships among the four estimators. Determining which method is best for public health will require additional analysis that focuses on the true alarm and false alarm rates using known vaccine-event associations. Evaluating the properties of these data mining methods will help determine the value of such methods in vaccine safety surveillance.     

Monitoring the safety of vaccines: assessing the risks.

The safety of vaccines, particularly the most widely used vaccines to which most children are exposed as infants and toddlers, has always been an extremely high priority for vaccine manufacturers and government agencies. Products intended for healthy people must be held to a high standard of safety assurance. In addition to the intense safety assessments conducted prior to licensure, post-marketing surveillance programmes are essential to identify and study possible risks that occur too rarely to have been identified in pre-licensure studies or that occur in populations not studied in pre-licensure studies. Studying rare risks of vaccines is more complex than for therapeutic products because the exposure is virtually universal for many vaccines, ensuring occurrence simply by chance of many adverse outcomes in temporal association with vaccination. In the US the Vaccine Safety Datalink (VSD), a consortium of managed care organisations, has been established to study more rigourously possible vaccine-associated risks. These risks may be identified through reports to the Vaccine Adverse Event Reporting System (VAERS), the nationwide passive surveillance programme, as well as other sources. The combination of passive surveillance and more structured case-control or cohort studies possible in the VSD has helped to both identify new vaccine risks and to provide reassuring evidence of lack of risk in other situations where concerns have been raised.     

Safety of anthrax vaccine: an expanded review and evaluation of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)

PURPOSE: To assess the safety of a licensed anthrax vaccine (AVA) given to more than 500,000 US military personnel, through review and medical evaluation of adverse events (AEs) reported to the Vaccine Adverse Event Reporting System (VAERS). METHODS: AEs were summarized by person, vaccine lot, type, frequency and impact. A Delphic approach was used to tentatively assess causality in an effort to detect serious AEs (SAEs) or other medically important AEs (OMIAEs) possibly attributable to AVA. RESULTS: The Anthrax Vaccine Expert Committee (AVEC) reviewed 1841 reports describing 3991 AEs (9.4 reports/10,000 doses of AVA) that were submitted to VAERS from 1Q1998 through 4Q2001. One hundred forty-seven reports described an SAE or OMIAE, of which 26 were tentatively rated as possible, probable or certain consequences of vaccination (injection-site reaction [12], 'anaphylactic-like reaction' [5] and eight other systemic AEs [1-2 each]). CONCLUSIONS: This review produced no evidence for an unusual rate of any SAE or OMIAE attributable to AVA. It supported an earlier impression that AVA may cause significant local inflammation and should be administered over the deltoid rather than the triceps to avoid direct or compression injury to the ulnar nerve. The subjects of VAERS reports tended to be older than all recipients of AVA. Females generally had and/or reported AEs more often than males, but transient articular reactions were surprisingly more common in males. Variations in the frequency or severity (as judged by hospitalization and/or loss of duty) of reported AEs did not suggest a significant problem with (1) a particular lot of AVA, (2) recurrent AEs after multiple doses or (3) vaccination of persons with a concomitant illness or those given other vaccines or medications.     

A review of the Vaccine Adverse Event Reporting System database

The Vaccine Adverse Event Reporting System (VAERS) is an epidemiological database that has been maintained by the FDA and Centers for Disease Control and Prevention (CDC) since 1990. Authors from the National Immunization Programme of the CDC have previously described an epidemiological technique to make qualitative and quantitative measurement in the VAERS database. Application of this technique by ourselves (with further refinements and additions) have resulted in numerous publications showing the VAERS database has good positive predictive value in evaluating vaccine safety concerns that are compatible with observations by many other authors who have analysed different databases. In conclusion, VAERS studies will be particularly critical in the evaluation of the safety of many new or radically changed vaccines expected to be introduced in the relative near future.     

Tracking vaccine lot lifecycles using reports to the vaccine adverse event reporting system (VAERS)

PURPOSE: There is currently no systematically available information available on how rapidly a specific lot of vaccine is used once distributed. We used data from reports to the Vaccine Adverse Event Reporting System (VAERS) to develop a proxy means of surveillance for the lifecycle of selected vaccine lots. METHODS: A convenience sample, consisting of selected lots of: diphtheria, tetanus, and acellular pertussis (DTaP), Haemophilus influenzae type b (Hib), Hepatitis B, and varicella vaccines, was selected for lifecycle analysis. Assuming that circulation of a vaccine lot is proportional to vaccine-specific adverse event (AE) reporting for that vaccine type, we constructed Gamma distributed usage models and compared them with lot-specific VAERS reports to estimate the actual lifecycle of lots in the system. RESULTS: Evidence of lot circulation was detected within 1-2 months, and a peak was observed 3-4 months after the vaccine release date for most of the study vaccines. Ninety percent of the vaccine doses in each lot were estimated to be used within 5-9 months of distribution. The length of time a vaccine lot was in use ranged from 5 to 17 months from earliest vaccination date. CONCLUSIONS: Our modeled and inferred administration of the selected lots of different vaccines were concordant. This method may be useful for spatial and temporal tracking of vaccine lot utilization.     

A review of the Vaccine Adverse Event Reporting System database

The Vaccine Adverse Event Reporting System (VAERS) is an epidemiological database that has been maintained by the FDA and Centers for Disease Control and Prevention (CDC) since 1990. Authors from the National Immunization Programme of the CDC have previously described an epidemiological technique to make qualitative and quantitative measurement in the VAERS database. Application of this technique by ourselves (with further refinements and additions) have resulted in numerous publications showing the VAERS database has good positive predictive value in evaluating vaccine safety concerns that are compatible with observations by many other authors who have analysed different databases. In conclusion, VAERS studies will be particularly critical in the evaluation of the safety of many new or radically changed vaccines expected to be introduced in the relative near future.     

Anti-cocaine vaccines: antibody protection against relapse

The past decade has seen the development of several vaccines against illicit-drugs. These include vaccines for producing antibodies against cocaine, heroin, methamphetamine and nicotine. The present focus is on anti-cocaine vaccines, as more research has been conducted with these vaccines than other vaccines targeted against a drug of abuse. Attention needs to be given to the structure of the hapten being conjugated, the characteristics of the carrier protein for conjugation with the hapten and the immunisation regimen for antibody production. These issues have an impact on the level of and variability in the anti-cocaine antibodies actively induced and, consequently, on the pharmacokinetic and pharmacodynamic properties of the vaccine. These issues also have an impact on the preclinical and clinical success of the vaccine in protecting against drug use and relapse. If an anti-cocaine vaccine is to be clinically useful, it must induce a sufficient level of antibody in the blood to prevent easy surmountability of protection by continued cocaine use and should be compatible with other treatment medications that may be simultaneously administered.     

Preventable mix-ups of tuberculin and vaccines: reports to the US Vaccine and Drug Safety Reporting Systems

BACKGROUND: Errors involving the mix-up of tuberculin purified protein derivative (PPD) and vaccines leading to adverse reactions and unnecessary medical management have been reported previously. OBJECTIVES: To determine the frequency of PPD-vaccine mix-ups reported to the US Vaccine Adverse Event Reporting System (VAERS) and the Adverse Event Reporting System (AERS), characterize adverse events and clusters involving mix-ups and describe reported contributory factors. METHODS: We reviewed AERS reports from 1969 to 2005 and VAERS reports from 1990 to 2005. We defined a mix-up error event as an incident in which a single patient or a cluster of patients inadvertently received vaccine instead of a PPD product or received a PPD product instead of vaccine. We defined a cluster as inadvertent administration of PPD or vaccine products to more than one patient in the same facility within 1 month. RESULTS: Of 115 mix-up events identified, 101 involved inadvertent administration of vaccines instead of PPD. Product confusion involved PPD and multiple vaccines. The annual number of reported mix-ups increased from an average of one event per year in the early 1990s to an average of ten events per year in the early part of this decade. More than 240 adults and children were affected and the majority reported local injection site reactions. Four individuals were hospitalized (all recovered) after receiving the wrong products. Several patients were inappropriately started on tuberculosis prophylaxis as a result of a vaccine local reaction being interpreted as a positive tuberculin skin test. Reported potential contributory factors involved both system factors (e.g. similar packaging) and human errors (e.g. failure to read label before product administration). CONCLUSIONS: To prevent PPD-vaccine mix-ups, proper storage, handling and administration of vaccine and PPD products is necessary.     

Vaccine adverse event reporting system (VAERS): Evaluation of 31 years of reports and pandemics’ impact

BackgroundVaccine adverse event reporting system (VAERS) was established in the United States (U.S.) as an early warning system with a main purpose of collecting post-marketing Adverse events following immunizations (AEFIs) reports to monitor the vaccine safety and to mitigate the risks from vaccines. During the coronavirus diseases 2019 (COVID-19) pandemic, VAERS got more attention as its important role in monitoring the safety of the vaccines. The aim of this study was to investigate VAERS patterns, reported AEFI, vaccines, and impact of different pandemics since its inception.MethodsThis was an observational study using VARES data from 2/7/1990 to 12/11/2021. Patterns of reports over years were first described, followed by a comparison of reports statistics per year. Furthermore, a comparison of incidents (death, ER visits, etc.) statistics over years, in addition to statistics of each vaccine were calculated. Moreover, each incident's statistics for each vaccine were calculated and top vaccines were reported. All analyses were conducted using R (Version 1.4.1717) and Excel for Microsoft 365.ResultsThere were 1,396,280 domestic and 346,210 non-domestic reports during 1990–2021, including 228 vaccines. For both domestic and non-domestic reports, year of 2021 had the highest reporting rate (48.52 % and 70.33 %), in addition a notable change in AEFIs patterns were recorded during 1991, 1998, 2000, 2006, 2009, 2011, and 2017. AEFIs were as follow: deaths (1.00 % and 4.08 %), ER or doctor visits (13.37 % and 2.27 %), hospitalizations (5.84 % and 27.78 %), lethal threat (1.42 % and 4.38 %), and disabilities (1.4 % and 7.96 %). Pyrexia was the top reported symptom during the past 31 years, except for 2021 where headache was the top one. COVID-19 vaccines namely Moderna, Pfizer-Biontech, and Janssen were the top 3 reported vaccines with headache, pyrexia, and fatigue as the top associated AEFIs. Followed by Zoster, Seasonal Influenza, Pneumococcal, and Human papillomavirus vaccines.ConclusionsThe large data available in VARES make it a useful tool for detecting and monitoring vaccine AEFIs. However, its usability relies on understating the limitations of this surveillance system, the impact of governmental regulations, availability of vaccines, and public health recommendations on the reporting rate.     

Non-clinical vaccine safety assessment

As vaccines are undoubtedly classified as pharmaceuticals, they have to be submitted to strict non-clinical safety evaluation. The context of their prophylactic use requires that every effort is made to ensure their safe use. Their safety evaluation is complex as they act through a multistage mechanism in which the vaccine by itself acts as a pro-drug, antibodies and activated lymphocytes being the actual effectors. Therefore, several potential toxicities must be considered: direct toxicity of the test article, toxicity linked to the pharmacodynamic activity of the vaccine, activation of pre-existing disorders, toxicity of contaminants and impurities and other adverse reactions due to interaction between the various components. Guidelines dealing with vaccines include general guidelines applicable to all pharmaceuticals, such as ICH S6, and also more specific documents which allow some flexibility in study design. Among the various studies, if single-dose studies are generally part of the quality control test battery, repeated dose studies are pivotal. The animal model and treatment schedule selection and the parameters investigated are critical for the relevance of this safety assessment. Immunological and safety pharmacology parameters should be adapted to the specific properties of vaccines and added to this type of study. Vaccines intended for pregnant women or women of child-bearing age require embryo-fetal and post-natal studies with an adapted design to obtain appropriate fetal and maternal exposure during gestation with continuation into the post-natal period. Tests exist to detect hypersensitivity or autoimmune reactions, but require further validation. In addition to this tailor-made approach, any adjuvant or active component added to the vaccine formulation necessitate their own assessment using studies routinely performed for new drugs. From this review, vaccine toxicology would appear to be a separate discipline on its own whose predictivity will be increased by new method development.     

Is vaccine therapy the future in cancer prevention?

One vaccine designed to prevent cancer by preventing a precursor infection is already in common use, and at least one more is in the latter stages of clinical development. These vaccines are part of a new era of cancer immunoprophylaxis. Several further vaccines are in preclinical and clinical development, targeted at preventing cancer precursor infections, and these should add to our ability to prevent this common human disorder. However, vaccines to prevent cancers not triggered by infection are a more remote prospect, for a variety of reasons.     

Vaccines: predicting the risk of allergy and autoimmunity

The field of vaccines is markedly evolving with the introduction and development of many new concepts and formulations, as well as new indications. Based on the current clinical experience, vaccines can be considered safe in most cases. Nevertheless, allergy and, to a lesser extent, autoimmunity have repeatedly been described or suspected as rare adverse consequences of human vaccines. The mechanisms of these adverse reactions are ill-elucidated, if at all. No animal models have been adequately standardized and validated to predict the risk of allergy and autoimmunity associated with vaccines. However, a number of existing models can be considered for use, but need refinement to be applied to vaccine evaluation. Finally, because the preclinical safety evaluation has not received much attention in the past, efforts should be paid to design specific and cost-effective procedures to meet the current expectations.     

基于真实世界的四价流感疫苗不良反应信号挖掘研究

目的挖掘四价流感疫苗的不良反应信号,为临床安全接种流感疫苗提供参考。方法利用报告比值比(ROR)法和比例报告比值比(PRR)法对美国疫苗不良事件报告系统(VAERS) 2013年至2018年的疫苗不良反应报告进行分析。结果 ROR法共得到222个信号,取信号较强的前50个不良反应信号,其中47个未在四价流感疫苗说明书中出现。结论四价流感疫苗的不良反应信号发生频次较高的集中在全身性损害,相关性较高的集中在肌肉与骨骼肌损害、中枢及外周神经系统损伤,尤其是颜面部外周神经损伤等。临床接种疫苗后,应及时关注接种者的面部外周神经损伤和肌肉骨骼肌损害的发生。     

Is vaccine therapy the future in cancer prevention?

One vaccine designed to prevent cancer by preventing a precursor infection is already in common use, and at least one more is in the latter stages of clinical development. These vaccines are part of a new era of cancer immunoprophylaxis. Several further vaccines are in preclinical and clinical development, targeted at preventing cancer precursor infections, and these should add to our ability to prevent this common human disorder. However, vaccines to prevent cancers not triggered by infection are a more remote prospect, for a variety of reasons.     

Surveillance systems and methods for monitoring the post-marketing safety of influenza vaccines at the Centers for Disease Control and Prevention

ABSTRACT

Introduction: Annual influenza vaccine safety monitoring is an important component of the influenza vaccination program in the United States to ensure that vaccines are safe, which is important for maintaining public trust in the national vaccination program. This is specially the case for influenza vaccines since the antigen composition of the viruses of which the vaccine is made often changes from one season to the next, based on the circulating strain of influenza virus.

Areas covered: This review describes the two surveillance systems used by the Centers for Disease Control and Prevention (CDC) to monitor the safety of influenza vaccines: 1) the Vaccine Adverse Event Reporting System (VAERS); and 2) the Vaccine Safety datalink (VSD).

Expert opinion: VAERS and VSD are used routinely to monitor the safety of influenza vaccines in the United States, and over the years they have demonstrated their value in monitoring vaccine safety since their implementation in 1990. Both systems, although different, complemented each other well to study febrile seizures in young children following influenza vaccination during the 2010–2011 influenza season. Other examples of potential safety concerns after influenza vaccines are also presented and discussed.     

Improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design: the Phacilitate Vaccine Forum, Washington D.C. 2011

The 9th Annual Vaccine Forum organized by Phacilitate in Washington D.C. 2011 brought together 50+ senior level speakers and over 400 participants representing all the key stakeholders concerning vaccines. The main focus of the meeting was to define priorities in the global vaccines sector from funding to manufacturing and evaluation of vaccine efficacy. A special session was devoted to improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design. The current regulatory approach to clinical assay specification, validation and standardization that enable more direct comparisons of efficacy between trials was illustrated by the success in meningococcal vaccine development. The industry approach to validation strategies was exemplified by a new serologic test used on the diagnostic of pneumococcal pneumonia. The application of the Animal Rule to bridge clinical and non-clinical studies in botulism has allowed significant progress in developing one of the first vaccines to seek approval under the FDA Animal Efficacy Rule. An example of pushing the boundaries in the correlation of immunological responses and efficacy points was represented by a recent cell-based influenza vaccine for which the same correlates of protection apply as for the traditional, egg-based flue vaccine. In the field of HIV phase 2b studies are underway, based on promising results obtained with some vaccine candidates. The conclusion of this session was that creativity in vaccine design and evaluation is beneficial and can lead to innovative new vaccine designs as well as to validated assays to assess vaccine efficacy.     

Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control

Influenza viruses of the H5N1 subtype cause an ever-increasing number of bird-to-human transmissions and a pandemic outbreak caused by these viruses is imminent. Therefore, the availability of safe and effective vaccines is highly desirable and their development considered a priority. However, using production and use of seasonal influenza vaccine as template for the production of pandemic H5N1 vaccines did not yield effective vaccines. High antigen doses were required to induce appreciable antibody responses. In addition, limited production capacity and long production times are other disadvantages of conventional influenza vaccine preparations. Here, we review recent developments that will contribute to a more rapid availability of sufficient doses of highly efficacious and safe pandemic influenza vaccines. The new developments include the establishment of novel methods to prepare vaccine strains, novel production technologies and the use of novel adjuvants and alternative vaccine formulations.     

埃博拉病毒疫苗最新研究进展

埃博拉病毒(Ebola virus,EBOV)是引起人类和非人灵长类动物严重出血热的最危险病原体之一,1976年首次得到报道.2014年撒哈拉以南非洲暴发的EBOV病的病死率高达90％.研究表明EBOV灭活疫苗无效,但多个新型EBOV候选疫苗已在临床前试验中显示有效,其中部分已进入临床试验.这些新型疫苗包括病毒载体疫苗、病毒样颗粒疫苗和核酸疫苗.此文对EBOV疫苗的研究进展做一综述.